After surviving events on the Helicarrier, S.H.I.E.L.D. Agent Phil Coulson puts together a small team of S.H.I.E.L.D. agents to handle strange new cases. They investigate Project Centipede, eventually uncovering that Centipede is backed by the organization Hydra, which has infiltrated S.H.I.E.L.D.

Following the destruction of S.H.I.E.L.D., Coulson and his team look to restore trust from the government and public while dealing with Hydra and the newly revealed Inhumans, people who possess special abilities. Coulson's work is further complicated by the appearance of another faction of S.H.I.E.L.D. agents who do not trust his leadership.

Coulson begins a secret mission to assemble a team of Inhumans to deal with new threats to the world, while Hydra returns its ancient banished Inhuman leader to Earth.